Drospirenone: Pharmacology and Pharmacokinetics of a Unique Progestogen

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Contraception 62 (2000) 29–38 Original research article Drospirenone: pharmacology and pharmacokinetics of a unique progestogen

Rolf Krattenmacher*

Berlex Laboratories, 300 Fairﬁeld Road, Wayne, NJ 07470 USA

Received 20 March 2000; received in revised form 18 May 2000; accepted 22 May 2000

Abstract

The pharmacology and pharmacokinetics of drospirenone, a unique progestogen, are reviewed in this paper. Unlike other progestogens, drospirenone, an analogue of spironolactone, has biochemical and pharmacologic proﬁles similar to endogenous progesterone, especially regarding antimineralocorticoid and antiandrogenic activities. Drospirenone counteracts the estrogen-induced stimulation of the renin- angiotensin-aldosterone system and blocks testosterone from binding to androgen receptors. Because of these characteristics, it has the potential to reduce body weight, blood pressure, and low-density lipoprotein levels and to enhance high-density lipoprotein levels. As a combination oral contraceptive, drospirenone with ethinyl estradiol is effective and has positive effects on weight and lipid levels. Additionally, it relieves menstrually related symptoms (e.g., negative affect and water retention) that are commonly observed with other combination oral contraceptives. Based on the biochemical and pharmacodynamic data, drospirenone appears to be a viable alternative to the currently available progestogens. © 2000 Elsevier Science Inc. All rights reserved.

Keywords: Drospirenone; Progestogen; Oral contraceptive; Renin-angiotensin-aldosterone system; premenstrual syndrome

1. Introduction taining these progestogens may be due, in part, to the absence of these specific antihormone characteristics Improving the safety and tolerability of oral contra- [1,7–9]. These effects include breast tenderness, weight ceptives (OCs) without affecting efficacy has been a gain, increased blood pressure (BP), and mood swings. major research goal for over 20 years. Developing new Adverse effects such as these are the major reason why progestogens has been considered one means of achiev- women discontinue the use of OCs [8]. ing this goal [1,2]. Ideally, a progestogen should have a Drospirenone is an analogue of the aldosterone antag- pharmacologic profile similar to progesterone. Currently onist, spironolactone, and is a unique progestogen [10]. available progestogens are structurally related to either The pharmacologic profile of drospirenone is more 19-nortestosterone (e.g., norethisterone, norethisterone closely related to that of progesterone, especially with acetate, levonorgestrel, gestodene, desogestrel, norgesti- regard to antimineralocorticoid and antiandrogenic activities, than that of any other synthetic progestogen [11– mate, and dienogest) or 17␣-hydroxyprogesterone (e.g., 14]. This suggests that adverse effects commonly ob- medroxyprogesterone acetate, megestrol acetate, chlor- served with combination OCs may be decreased with an madinone acetate, and cyproterone acetate) [3.4]. While OC containing drospirenone. In a recent study, the con- some of these agents have antiandrogenic properties traceptive efficacy and adverse effects of drospirenone/ (e.g., dienogest, cyproterone acetate, megestrol acetate, ethinyl estradiol combination treatment were evaluated and chlormadinone acetate), they all lack antimineralo- with favorable results [2]. corticoid activity when used in clinically relevant dos- The purpose of this article is to review the distinctive ages [3,5,6]. Adverse effects associated with OCs con- biochemical and pharmacologic characteristics and pharmacokinetics of drospirenone. In addition, contraceptive efficacy and the potential health benefits beyond contraception * Correspondence. Tel.: ϩ1-973-305-5324; fax: ϩ1-973-305-5340. associated with drospirenone/ethinyl estradiol will be E-mail address: [email protected] (R. Krattenmacher). discussed.

Fig. 1. Chemical structures of spironolactone and drospirenone and major drospirenone plasma metabolites. (Data on ﬁle, Berlex Laboratories, Wayne, NJ, USA.)

2. Biochemistry says. Relative binding affinity values of these reference compounds were arbitrarily set at 100%. Results of both the Drospirenone (6␤,7␤,15␤,16␤-dimethylene-3-oxo-17␣- animal and human steroid receptor binding assays are sum- pregn-4-ene-21,17 carbolactone) is an analogue of the an- marized in Table 1. Of note, (1) drospirenone demonstrated timineralocorticoid spironolactone (Fig. 1) that is synthe- a relative binding affinities of 19% to the human and 40% to sized from androstenolone [10,15,16]. A comprehensive, the rabbit progesterone receptor; (2) drospirenone and pro- comparative biochemical characterization of drospirenone gesterone have high relative binding affinities for the min- and progesterone examined their interaction with a series of eralocorticoid receptor (500% and 1000% for the human classical steroid hormone receptors such as the progester- receptor for drospirenone and progesterone, respectively; one, androgen, glucocorticoid, mineralocorticoid, and estro- both 100% for the rat receptor); (3) both progestogens have gen receptors [10]. The relative binding affinities of dro- Յ3% relative binding affinity to the androgen receptor in all spirenone and progesterone to these receptors were models; (4) drospirenone exhibits a low relative binding determined using cytosol fractions containing the expres- affinity to the glucocorticoid receptor (1% and 3% for the sion vector for the respective animal (rat or rabbit) [10] or animal and human receptor, respectively), whereas proges- human steroid receptor. (Data on file, Schering AG, Berlin, terone has some binding affinity to this receptor (11% and Germany.) The radiolabeled reference compounds for the 35% for the animal and human receptor, respectively); and progesterone, androgen, mineralocorticoid, glucocorticoid, (5) neither drospirenone nor progesterone demonstrate sig- and estrogen receptors were progesterone, methyltrien- nificant binding to the estrogen receptor [10]. (Data on file, olone, aldosterone, dexamethasone, and estradiol, respec- Schering AG, Berlin, Germany.) In contrast, other proges- tively, in both the human and animal receptor binding as- togens such as gestodene, 3-ketodesogestrel (active metab- R. Krattenmacher / Contraception 62 (2000) 29–38 31

Table 1 Relative binding afﬁnities (RBA) of progesterone and drospirenone to steroid hormone receptors [10]a

RBA (%) Receptor Progesteron Androgen Mineralocorticoid Glucocorticoid Estrogen recptor receptor receptor receptor receptor

Human Rabbit Human Rat Human Rat Human Rat Human Rat Drospirenone 19 40 2 1 500 100 3 1 Ͻ0.5 nc* Progesterone 100 100 3 1 1000 100 35 11 Ͻ0.5 nc

aHuman data on file, Schering AG, Berlin, Germany. *nc ϭ no competition. The radiolabeled reference compounds for the progesterone, androgen, mineralocorticoid, glucocorticoid, and estrogen receptors were progesterone, methyltrienolone, aldosterone, dexamethasone, and estradiol, respectively in both the human and animal receptor binding assays. RBA vales of these reference compounds were arbitrarily set at 100%. olite of desogestrel), and levonorgestrel have different re- spirenone has antiandrogenic activity which is explained by ceptor-binding profiles than drospirenone and progesterone competitive binding to the androgen receptor and is intrinsic [17]. All three progestogens have demonstrated higher bind- to its molecular structure; this direct antiantiandrogenic ef- ing affinities to both the progesterone and androgen receptor fect is in addition to the more indirect antiandrogenic effect than progesterone or drospirenone. Additionally, levonorg- of progestogens in general, that is mainly explained by the estrel and 3-ketodesogestrel have lower binding affinities to suppression of androgen production from the adrenals or the mineralocorticoid receptor than either progesterone or ovaries. Drospirenone shows no glucocorticoid and antiglu- drospirenone, whereas gestodene has a greater binding af- cocorticoid activity, whereas progesterone exhibits weak finity to this receptor than progesterone or drospirenone. glucocorticoid-receptor–mediated agonistic activity but not The effects of drospirenone and progesterone on andro- antagonist activity [10]. Overall, the results from the ste- gen-, glucocorticoid-, and mineralocorticoid-receptor–me- roid-binding and transactivation assays demonstrate that the diated induction of transcription were also evaluated using biochemical profile of drospirenone is similar to that of in vitro transactivation assays [10]. These assays were per- progesterone, especially regarding its antimineralocorticoid formed in CV-1 cells transfected with either androgen or and antiandrogenic activities [10]. This profile distinguishes glucocorticoid receptors and a reporter plasmid containing drospirenone from other synthetic progestogens currently mouse mammary tumor promotor virus or COS 1 cells used in OCs (Table 2) [5,6,18]. transfected with mineralocorticoid receptor and the identical viral promotor [10]. The results showed that (1) drospirenone and progesterone inhibit aldosterone-induced 3. Pharmacology and bioactivity mineralocorticoid activity and weakly induce reporter gene transcription on their own; (2) both progestogens have no The progestational activity of drospirenone has been androgenic activity but display antiandrogenic activity in analyzed by evaluating its antigonadotropic and endometri- terms of inhibition of androgen-receptor–mediated tran- um-transforming capabilities [11,14]. In male cynomolgus scription in a dose-dependent manner [10]. The receptor- monkeys treated with drospirenone 4 mg/kg/day (orally mediated inhibition of transcription reflects that dro- [p.o.]) on days 5, 7, 10, 12, and 14, drospirenone showed a

Table 2 Pharmacologic proﬁle of drospirenone and other progestogens in animal models [5,6,18]

Pharmacologic activitiesa Progestogenic Androgenic Antiandrogenic Antimineralocorticoid Glucocorticoid Progesterone ϩϪ(ϩ) ϩϪ Drospirenone ϩϪϩϩ Ϫ Cyproterone acetate ϩϪϩϪ (ϩ) Desogestrelb ϩ (ϩ) ϪϪ Ϫ Dienogest ϩϪϩϪ Ϫ Gestodene ϩ (ϩ) Ϫ (ϩ) Ϫ Levonorgestrel ϩ (ϩ) ϪϪ Ϫ Norgestimatec ϩ (ϩ) ϪϪ Ϫ

a (ϩ) indicates negligible at therapeutic dosages; Ϫ, no effect; ϩ, distinct effect. b Active metabolite is 3-ketodesogestrel. c Main metabolites are levonorgestrel-3-oxime and levonorgestrel. 32 R. Krattenmacher / Contraception 62 (2000) 29–38

strong antigonadotropic effect by significantly reducing lu- antimineralocorticoid activity, which is not considered clin- teinizing hormone levels compared to the pretreatment ically relevant in contraceptive dosages [13]. phase [11,14]. Additionally, endometrial transformation Young women on a constant moderately low sodium and tests using ovariectomized rabbits initially treated for 6 potassium diet were treated with drospirenone 2 mg from consecutive days with estradiol (5 ␮g/animal; subcutane- day 8 to day 13 of their menstrual cycle and evaluated for ously [s.c.] or p.o.) and followed by a 5-day treatment of sodium and potassium excretion [12]. Those on dro- drospirenone (range, 0.1 to 1.0 mg/animal; s.c. or p.o.) spirenone had greater sodium excretion than women treated demonstrated marked endometrial transformation at a daily with placebo, except for the third day of treatment; the dosage of drospirenone 0.3 mg/animal [11,14]. The thresh- potassium excretion did not differ between the two groups. old dose for endometrial reactions (McPhail value of 1.5) Sodium excretion in the drospirenone-treated group rose ϩ occurred in the dose range of 0.1 to 0.3 mg/animal (s.c.) from a mean of 79.6 to 98.6 mmol Na /day during drug [11,14]. The results from these animal models are consistent treatment. The difference between average sodium excre- with results from receptor-binding assays and demonstrate tion rates of women treated with drospirenone and placebo that drospirenone has progestogenic activity. was close to significance (98.6 mmole/24 h and 81.8 ϭ Inhibition of ovulation by drospirenone alone or in com- mmole/24 h, respectively; p 0.053). Weight loss was bination with ethinyl estradiol 30 ␮g has been demonstrated slightly greater with drospirenone treatment than placebo in humans [19]. Patients had documented normal ovulatory treatment [12]. Drospirenone also significantly increased function in their pretreatment cycle. Drospirenone alone plasma renin activity and plasma and urinary aldosterone was assessed over 3 treatment cycles in 48 women random- during treatment [12]. ized to dosages of 0.5, 1, 2, and 3 mg in a dose ranging A rise in sodium excretion, plasma renin activity, and study. Dose-dependant efficacy in ovarian suppression was plasma and urinary aldosterone levels has been noted during shown. Incidence of ovarian ripening was 9% and 42% in 3 the luteal phase of the menstrual cycle. These effects are mg and 2 mg drospirenone groups, respectively. Incidence thought to be due to the antimineralocorticoid activity of progesterone [12]. A dosage of drospirenone 2 mg admin- of complete ovarian suppression was 91% and 50% in the 3 istered to normal, healthy menstruating women from day 5 mg and 2 mg groups, respectively. All subjects in the 3 mg to day 25 inhibited ovulation and prevented the rise in group were anovulatory, whereas 1 patient in each of the progesterone [12]. In contrast to cyproterone acetate, a pro- lower dosage groups ovulated. Efficacy in ovulation inhibi- gestogen with no antimineralocorticoid activity, dro- tion of drospirenone 2 mg or 3 mg combined with ethinyl spirenone induced natriuresis and increased plasma renin estradiol 30 ␮g was assessed in 52 women over 3 treatment activity and aldosterone levels during the follicular phase of cycles. Mean values of luteinizing hormone, follicle stimu- the menstrual cycle compared to that of the untreated con- lating hormone, 17␤-estradiol and progesterone serum lev- trol cycle (Fig. 2). Preliminary studies have demonstrated els were suppressed during all treatment cycles with the that drospirenone (2 or 4 mg/day) in combination with combination of drospirenone 2 mg or 3 mg and ethinyl ethinyl estradiol (30 ␮g/day) increases urinary sodium ex- ␮ estradiol 30 g, compared to pre- and post-treatment cycles. cretion, which is, however, compensated for by increases in In the 2 mg group, escape ovulation occurred in 1 cycle for plasma aldosterone and angiotensin II levels throughout the each of three patients; complete inhibition of ovulation was menstrual cycle [20]. The natriuresis and rise in plasma observed in 57 of 69 cycles. In the 3 mg group, none of the renin activity and plasma and urinary aldosterone levels women ovulated and complete ovulation inhibition was induced by drospirenone in the follicular phase is similar to observed in 62 of 69 cycles. that induced by progesterone in the luteal phase of the The effect of drospirenone on factors influenced by min- menstrual cycle [3,12]. eralocorticoid activity [e.g., electrolyte and water balance, Drospirenone has been shown to have no clinically sig- weight, and blood pressure (BP)] was examined in animal nificant effects on BP in animal and human studies. During models and humans. Ovariectomized rats fed on a low- a 4-week treatment with drospirenone (2 mg/day), BP did sodium diet treated with drospirenone or spironolactone not change in spontaneously hypertensive male rats, (each, 1 to 10 mg/animal/day) were evaluated for sodium whereas equipotent doses of levonorgestrel and cyproterone and potassium excretion [11,14]. Drospirenone was more acetate increased BP in these animals [21]. Similarly, dro- ϩ ϩ effective than spironolactone in increasing the Na /K ex- spirenone had only a slight effect on systolic BP and no cretion rate and was shown to be a long-term antimineralo- effects on diastolic BP in normotensive female rats [22]. BP corticoid, as a dosage of 10 mg/animal/day produced a and body weight were also evaluated in normal, healthy sustained stimulation of this electrolyte excretion ratio [11]. women who received either drospirenone 3 mg with varying Similar studies have shown that progestogens like levonor- doses of ethinyl estradiol (15, 20, and 30 ␮g) or levonorgestrel, norethisterone acetate, 3-ketodesogestrel, and gestrel 150 ␮g with ethinyl estradiol 30 ␮g for 6 months cyproterone acetate have neither antimineralocorticoid ac- [16]. Drugs were taken from day 1 to day 21 of the men- tivity nor mineralocorticoid activity. Gestodene, however, is strual cycle, followed by a pill-free interval of 7 days. devoid of mineralocorticoid activity but has a rather low Between the pretreatment cycle and the sixth treatment R. Krattenmacher / Contraception 62 (2000) 29–38 33

Fig. 2. Sodium excretion, plasma renin activity, plasma aldosterone levels, and aldosterone excretion in the first and second halves of the untreated control cycle and treatment cycles. *p ϭ 0.05; **p ϭ 0.01. Adapted with permission from J Clin Endocrinol Metabolism [12]. cycle, the mean body weight decreased by 0.8 to 1.7 kg in to that of the levonorgestrel/ethinyl estradiol-treated group the drospirenone/ethinyl estradiol-treated groups, whereas it were significant (all, p Ͻ0.05) [16]. In addition, systolic and increased 0.7 kg in the levonorgestrel/ethinyl estradiol- diastolic BP decreased by 1 to 4 mm Hg in groups treated treated group. The differences in the body weight change of with drospirenone and ethinyl estradiol, whereas it in- the drospirenone/ethinyl estradiol-treated groups compared creased by 1 to 2 mm Hg in the group treated with levonor- 34 R. Krattenmacher / Contraception 62 (2000) 29–38 gestrel and ethinyl estradiol. The change in systolic pressure Subsequent pharmacokinetic studies of drospirenone in man in the group treated with drospirenone 3 mg and ethinyl demonstrated that its absorption is rapid and complete, with estradiol 15 ␮g, and the changes in the diastolic pressures in peak plasma concentrations of drospirenone occurring the groups treated with drospirenone 3 mg and ethinyl within 1 to 2 hours after oral administration. (Data on file, estradiol, either 15 or 30 ␮g, were significantly different Berlex Laboratories, Wayne, NJ, USA.) The absolute bio- from the corresponding changes in the levonorgestrel/ethi- availability of drospirenone after oral administration to nyl estradiol-treated group (all, p Ͻ0.05) [16]. Overall, the young, healthy women was on average 76%. There is a results from these in vivo studies clearly show that the data linear relationship between the dose of drospirenone (range, from the receptor-binding and transactivation assays trans- 1 to 10 mg) and the pharmacokinetics of drospirenone. late into antimineralocorticoid activity of drospirenone in Steady-state is achieved after about 7 daily administrations animals and humans. of drospirenone 3 mg in combination with ethinyl estradiol The effect of drospirenone on factors influenced by an- 30 ␮g. The average maximum drospirenone plasma concen- drogenic activity was examined in animal models and hu- tration ranges between 60 and 87 ng/mL, and the mean mans. Animal studies demonstrated that drospirenone has drospirenone trough level ranges between 20 and 25 ng/mL. antiandrogenic activity in terms of its effects on the growth Plasma levels of drospirenone decline biphasically. After of accessory sex glands in androgen-treated juvenile cas- oral administration the mean half-lives are about 2 hours for trated rats. Drospirenone at dosages ranging from 0.1 to 10 the distribution phase and range from 25 to 33 hours for the mg/animal/day (s.c.) caused a dose-dependent inhibition of disposition phase. Approximately 95% to 97% of dro- the growth of both seminal vesicles and the prostate upon 7 spirenone is bound to serum protein, thought to be albumin. days’ application [10,11,14], Similar effects were seen with Drospirenone does not bind to sex-hormone-binding glob- progesterone at dosages ranging from 0.3 to 30 mg/animal/ ulin or corticosteroid-binding globulin and does not atten- day (s.c.) [10]. uate the ethinyl estradiol induced increase in these proteins. It has been demonstrated that combined oral contracep- Following oral or intravenous administrations, dro- tives reduce ovarian and adrenal production of testosterone spirenone is extensively metabolized. The major plasma and its precursors both by direct inhibition of enzymes metabolites of drospirenone are the acid form of dro- involved in their biosynthesis and indirectly through sup- spirenone generated by the opening of the lactone ring and pression of gonadotropin secretion [18,23]. Slight reduction the 4,5-dihydro-drospirenone-3-sulfate (Fig. 1). The major of ovarian androgen production has also been shown with metabolites are generated independently of the cytochrome the combination of drospirenone and ethinyl estradiol in P450 enzyme system. Excretion of drospirenone is nearly normal healthy women. (Data on file, Schering, AG, Berlin, complete after 10 days with trace amounts of drospirenone Germany.) excreted unchanged in urine and feces. At least 20 different An antiandrogenic effect has also been observed in metabolites are observed in urine and feces. Less than 10% women administered drospirenone 3 mg with ethinyl estra- of the metabolites in urine are freely extractable, while diol (15 to 30 ␮g) [16]. These combination treatments about 38% to 47% are excreted as glucuronide and sulfate produced increases in high-density cholesterol levels conjugates. In feces, about one-third of the metabolites are (range, 9% to 23%) and triglyceride levels (range, 47% to freely extractable and about 17% to 20% are excreted as 73%) above baseline compared to levonorgestrel 150 ␮g glucuronides and sulfates. and ethinyl estradiol 30 ␮g treatment (12% and unchanged from baseline, respectively). The differences in high-density cholesterol and triglyceride levels with the drospirenone 5. A new OC with drospirenone combinations are significantly different from the corresponding changes with the levonorgestrel combination (all, Recently Yasmin (Berlex Laboratories, Wayne, NJ, p Ͻ0.05). Conversely, drospirenone/ethinyl estradiol treat- USA), a new low-dose OC tablet containing drospirenone 3 ment decreases low-density cholesterol levels below base- mg and ethinyl estradiol 30 ␮g, was evaluated in a year- line level (14% to 20%) compared to levonorgestrel/ethinyl long, open-label, multicenter study for contraceptive effi- estradiol treatment, which had no effect. The results from cacy and safety [2]. The results showed Yasmin is an ef- these studies involving both animals and humans support fective, safe, and well-tolerated OC. One pregnancy previous data obtained with receptor-binding and transacti- occurred in 3201 cycles of 326 subjects; this subject re- vation assays that show drospirenone has antiandrogenic ported 1 intake error. After correcting for cycles without activity. recorded use of other contraceptives (3192 cycles), the Pearl Index was 0.4. The pregnancy ratio was 0.46 since 1 pregnancy occurred among the 220 subjects completing 13 cy- 4. Pharmacokinetics cles without using alternative contraception. No serious adverse events related to the contraceptive occurred. Addi- Drospirenone was initially detected and identified during tionally, 71% of subjects (230/326) reported at least one pharmacokinetic studies of spirorenone in the monkey [26]. adverse event during the study, and 6% of subjects (20/326) R. Krattenmacher / Contraception 62 (2000) 29–38 35

Fig. 3. Mean changes in menstrually related symptoms from baseline to cycle 6 for the three phases of the menstrual cycle. The three phases include the premenstrual phase (4-day period prior to menstruation), menstrual phase (ﬁrst through last day of menstruation), and postmenstrual phase (remainder of the cycle). Reprinted with permission from Contraception [2].

Fig. 4. Mean (SD) changes from baseline weight by cycle. Reprinted with permission from Contraception [2]. 36 R. Krattenmacher / Contraception 62 (2000) 29–38

Fig. 5. The proposed effects of drospirenone on physiologic mechanisms. discontinued the study because of adverse effects. Emo- of 1.5% or less, were the most frequently reported adverse tional lability, headache, nausea, dysmenorrhea, intermen- events cited for discontinuation. The incidence of these strual bleeding, and depression, that occurred at frequencies adverse events is comparable to that of other low-dose R. Krattenmacher / Contraception 62 (2000) 29–38 37 combination OCs; the antimineralocorticoid actions of dro- duced effects from the activation of the renin-angiotensin- spirenone would not be expected to impact the occurrence aldosterone system. In contrast, other available combined of these particular side effects [2]. OCs contain progestogens without antimineralocorticoid ac- During the same open-label study, the Menstrual Distress tivity and are frequently associated with adverse effects. Questionnaire [27] was adapted and used to assess menstrually related symptoms such as impaired concentration, negative affect, water retention, increased appetite, feelings of 6. Conclusions well-being, and undesirable hair change during three phases of the menstrual cycle (i.e., premenstrual, 4 days prior to The reviewed in vitro and in vivo animal studies show menstruation; menstrual, first through the last day of men- that drospirenone is a unique progestogen which has a struation; and postmenstrual, remainder of the cycle) [2]. biochemical and pharmacologic profile that closely resem- For water retention and negative affect, there was a statis- bles natural progesterone [10]. Unlike other currently avail- tically significant decrease from baseline to cycle 6 for all able synthetic progestogens derived from 17␣-hydroxypro- subjects in all phases of the menstrual cycle (Fig. 3). The gesterone or 19-nortestosterone, drospirenone demonstrates severity level of increased appetite was significantly lower both antimineralocorticoid and antiandrogenic activities at cycle 6 compared to baseline for all phases of the men- [11]. As such, drospirenone is a viable progestogenic alter- strual cycle, except the postmenstrual phase. There were no native that may, in some cases, be preferable to other significant changes for impaired concentration, undesirable choices. The actions of this unique progestogen in 3 phys- hair change, or feelings of well-being throughout the entire iologic pathways are summarized in Fig. 5. First, the pro- menstrual cycle (Fig. 3). Overall, drospirenone has a favor- gestogenic action results in inhibition of ovulation [2,11, able impact on the common menstrual cycle symptoms cited 14]. Second, the antiandrogenic activity of drospirenone above. These symptoms are often reported among patients could lead to suppression of unwanted symptoms such as suffering from premenstrual syndrome. acne and hirsutism through blockade of androgenic recep- Effects of drospirenone and ethinyl estradiol on weight, tors in the skin [6]. Finally, the antimineralocorticoid activ- BP, and lipids were also assessed in this study [2]. There ity of drospirenone balances the aldosterone-stimulating was a trend toward weight loss in cycles 1, 3, and 9, whereas mineralocorticoid effect of estrogens (e.g., ethinyl estradiol) ϭ significant weight loss occurred at cycle 6 (p 0.025). and may reduce estrogen-induced sodium and water reten- ϭ Weight gain, however, was significant at cycle 13 (p tion. Therefore, Yasmin, an effective and safe low-dose OC 0.0319; Fig. 4). During the study, BP remained within containing drospirenone and ethinyl estradiol, provides normal limits and no significant changes from baseline in health benefits beyond contraception. These benefits include mean systolic or diastolic BP occurred. Finally, lipids also a favorable impact on menstrually related symptoms (e.g., remained within normal limits throughout the study, but water retention and negative affect) and a favorable profile total cholesterol, triglycerides, high-density lipoprotein, and with respect to skin, weight, and lipids. the ratio of high-density lipoprotein to low-density lipoprotein showed significant increases from baseline at cycle 13 (p Ͻ0.0001). Thus, drospirenone/ethinyl estradiol OC has a favorable profile with respect to weight and lipids [2]. References Estrogenic components of OCs can contribute to many of [1] Elstein M, Furniss HA. Advances in oral hormonal contraception. their reported adverse effects [3]. Estrogens such as ethinyl Zentralbl Gynaekol 1995;117:559–65. estradiol, a common component of OCs, can stimulate the [2] Parsey KS, Pong A. 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